Neuroscience and Biobehavioral Reviews 47 (2014) 578–591

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Childhood adversity and neural development: Deprivation and threat

as distinct dimensions of early experience夽
Katie A. McLaughlin a,∗,1 , Margaret A. Sheridan b,1 , Hilary K. Lambert a
a
Department of Psychology, University of Washington, Seattle, WA, United States
b
Division of Developmental Medicine, Boston Children’s Hospital, Harvard Medical School Boston, MA, United States

a r t i c l e i n f o a b s t r a c t

Article history: A growing body of research has examined the impact of childhood adversity on neural structure and
Received 22 April 2014 function. Advances in our understanding of the neurodevelopmental consequences of adverse early
Received in revised form environments require the identification of dimensions of environmental experience that influence neu-
30 September 2014
ral development differently and mechanisms other than the frequently-invoked stress pathways. We
Accepted 15 October 2014
propose a novel conceptual framework that differentiates between deprivation (absence of expected
Available online 25 October 2014
environmental inputs and complexity) and threat (presence of experiences that represent a threat to
one’s physical integrity) and make predictions grounded in basic neuroscience principles about their dis-
Keywords:
Childhood adversity
tinct effects on neural development. We review animal research on fear learning and sensory deprivation
Neural development as well as human research on childhood adversity and neural development to support these predictions.
Adverse childhood experience We argue that these previously undifferentiated dimensions of experience exert strong and distinct influ-
Deprivation ences on neural development that cannot be fully explained by prevailing models focusing only on stress
Trauma pathways. Our aim is not to exhaustively review existing evidence on childhood adversity and neural
Threat development, but to provide a novel framework to guide future research.
Fear learning © 2014 Elsevier Ltd. All rights reserved.

Contents

1. Distinguishing between deprivation and threat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580

2. Deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
2.1. Predictions based on animal literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
2.1.1. Proliferation and pruning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
2.1.2. Visual deprivation as early experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
2.1.3. Global deprivation in animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
2.2. Consistency with evidence from human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
3. Threat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
3.1. Predictions based on animal literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
3.1.1. Fear learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
3.1.2. Effects of early threat on fear learning circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
3.2. Consistency with human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
4. Recommendations for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587

夽 This research was supported by grants from the National Institutes of Health (K01-MH092526 and R01-MH103291 to McLaughlin and K01-MH092555 to Sheridan).
∗ Corresponding author. Tel.: +1 206 616 7863.
E-mail address: mclaughk@uw.edu (K.A. McLaughlin).
1
Please note that these authors contributed equally to this work.

http://dx.doi.org/10.1016/j.neubiorev.2014.10.012
0149-7634/© 2014 Elsevier Ltd. All rights reserved.
 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
There has been a veritable explosion of research in the last
decade into the long-term consequences of exposure to child-
hood adversity. The terms ‘childhood adversity’, ‘adverse childhood
experience’, and ‘early life stress’ have been used to refer to a broad
set of negative exposures during childhood, ranging from physical
and sexual abuse to institutional rearing and chronic poverty (Anda
et al., 2006; Burghy et al., 2012; Cohen et al., 2013). Evidence from
population-based epidemiological studies indicates that childhood
adversity is common and associated strongly with the subsequent
onset of psychopathology not only in childhood, but also in ado-
lescence and adulthood (Cohen et al., 2001; Green et al., 2010;
Kessler et al., 1997; McLaughlin et al., 2012). Individuals who have
been exposed to adverse childhood experiences are at elevated risk
of developing a wide range of mental disorders, including mood,
anxiety, behavior, and substance use disorders. Importantly, expo-
sure to childhood adversity has been shown to explain more than
30% of mental disorders in the U.S. population (Green et al., 2010;
McLaughlin et al., 2012), underscoring the significance of these
experiences in shaping population-level mental health.
The strong and pervasive relationship between adverse child-
hood experiences and psychopathology has generated considerable
interest in identifying the underlying mechanisms that explain
these associations. However, identifying central mechanisms has
proved difficult, because different types of adverse experiences
frequently co-occur, meaning that most individuals exposed to
childhood adversity have experienced multiple adverse experi-
ences (Dong et al., 2004; Finkelhor et al., 2007; Green et al., 2010;
McLaughlin et al., 2012). Recognition of the co-occurring nature of
adverse childhood experiences has resulted in a shift from focus-
ing on single types of adversity, such as parental death, divorce,
abuse, and neglect (Chase-Lansdale et al., 1995; Dubowitz et al.,
2002; Fristad et al., 1993; Mullen et al., 1993; Wolfe et al., 1994), to
examining the associations between number of adverse childhood
experiences and psychopathology (Arata et al., 2007; Dube et al.,
2003; Edwards et al., 2003; but see also Humphreys and Zeanah,
2014 for a recent alternative approach). The fundamental lesson
from this research has been that as childhood adversities increase,
the likelihood of psychopathology increases. While this has proved
valuable for identifying children in need of intervention, it has led
to an oversimplification of the boundaries between distinct types
of environmental experience and has done little to uncover the core
underlying mechanisms through which adversity increases risk for
psychopathology.
Here we propose that cognitive neuroscience provides a
powerful set of tools that will allow us to most fruitfully iden-
tify the developmental pathways linking childhood adversity to
psychopathology and that examining the imprint of environ-
mental experience on neural structure and function will help to
resolve some of the challenges inherent in studying complex and
co-occurring exposures. Indeed, one of the basic principals of neu-
roscience, developed and elaborated over the last half century, is
that early experience shapes the structure and subsequent function
of the brain. A small but rapidly growing body of work has begun
to examine the impact of childhood adversity on neural develop-
ment (Hackman and Farah, 2009; Hart and Rubia, 2012). However,
to date most existing work has conceptualized adverse childhood
experiences purely within a stress perspective, which has hin-
dered the identification underlying dimensions of environmental
experience that might influence neural structure and function in
distinct ways (but see Rao et al., 2011 for a counter example).
Here we argue that the distinct neural effects of different dimen-
sions of experience have often been oversimplified or ignored.
Extant research has almost universally defined childhood adversity
according to broad descriptive categories (i.e., abuse, neglect, insti-
tutionalization, poverty) or has examined even broader constructs
that combine diverse forms of adversity together, often referred to
579
as ‘early life stress’ (Burghy et al., 2012; Cohen et al., 2006; Gatt et al.,
2009). This term has been used to refer to such disparate experi-
ences as parental psychopathology, abuse, poverty, marital conflict,
and institutional rearing. This approach not only obscures mean-
ingful differences between these types of experiences that are likely
to have important implications for understanding their effects on
neural development but also implicitly suggests that very different
types of environmental experiences influence brain development
through the same underlying mechanisms. This lack of specificity
both with regard to the measurement of environmental experience
and the impacts on brain development constitutes a critical bar-
rier to identifying the pathways through which childhood adversity
impacts neural development and, ultimately, psychopathology.
Current conceptualization of the impact of childhood adversity
on neural development has focused almost exclusively on stress
pathways and allostatic load (Burghy et al., 2012; Cohen et al.,
2013). The stress model has been described in detail in numer-
ous previous papers (see McEwen, 2012). Briefly, activation of the
hypothalamic–pituitary–adrenal (HPA) axis results in the release
of glucocorticoids, which can lead to structural and functional
changes in brain regions with high concentrations of glucocorticoid
receptors, including the hippocampus, amygdala, and prefrontal
cortex (PFC) (McEwen, 2012). The HPA axis is a plastic system and
exposure to extreme or chronic stress can lead to changes in the
functioning of this system, resulting in excessive or blunted gluco-
corticoid release and related downstream structural consequences
in the brain (McEwen, 1998, 2012). Extensive evidence suggests
that early exposure to adverse environments can disrupt the devel-
opment and functioning of the HPA axis (Gunnar and Quevedo,
2007), and this is the primary mechanism through which it is
often argued that adverse experiences shape neural structure and
function. Focusing only on this mechanism is problematic, how-
ever, as adversity sometimes appears to have a remarkably broad
impact on neurodevelopment. For example, children exposed to
institutional rearing exhibit widespread cortical thinning in the
superior and inferior parietal cortex (McLaughlin et al., 2014), and
children exposed to neglect and poverty often have deficits in lan-
guage abilities (Farah et al., 2006; Hildyard and Wolfe, 2002) and
accompanying differences in neural function supporting language
function (Raizada et al., 2008). Neither of these patterns is an obvi-
ous consequence of HPA axis activation or cortisol.
However, this evidence is by no means conclusive. Glucocor-
ticoids are only one of many mediators that work together to
modulate brain development following stress. The coordinated
actions of these mediators are dependent on the state of differentia-
tion of each brain region and are highly region and cell type specific
when stress occurs. Indeed, a host of mechanisms of hormone
action reveal that the whole brain is a target for the modulatory
effects of stress and other hormones via genomic and non-genomic
receptors (Liston et al., 2013; McEwen, 2010; Popoli et al., 2012)
As such, it is important to acknowledge that the effects of stress
are not fully mediated by cortisol (the most common marker of
HPA axis activation in human research) and that cortisol actions
on their own do not explain how stress affects gene expression or
neuronal plasticity (Gray et al., 2013). Thus, although it is possible,
given the potentially wide variety of effects that stress can have on
the brain, that the changes described above are the downstream
effect of stress exposure, it is also possible – and we argue, likely
– that alternative mechanisms explain these effects of childhood
adversity on neural development. Investigating these mechanisms
first requires a novel method of describing and measuring different
forms of childhood adversity.
We argue here that the field must move beyond the prevailing
approach to one that attempts to distill complex adverse expe-
riences into their core underlying dimensions, and we propose
a conceptual framework for doing so. Specifically, our model
580 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
differentiates between experiences of deprivation (i.e., the absence
of expected environmental inputs and complexity) and threat
(i.e., the presence of experiences that represent a threat to one’s
physical integrity) and provides predictions and preliminary evi-
dence grounded in basic neuroscience principles and mechanisms
drawn from animal research on sensory deprivation and fear
learning about the expected effects of each of these dimensions
of experience on neural structure and function. Our aim is not
to exhaustively review existing evidence on early adversity and
neural development in humans or animals, but to provide a novel
conceptual framework to guide future research.
Importantly, we do not propose that deprivation and threat are
the only dimensions of early experience that are important or that
all types of childhood adversity can be conceptualized solely along
these dimensions. For example, institutional rearing involves the
complete absence of an attachment figure early in development,
(Tottenham, 2012). This lack of species-typical expectations of the
presence of an attachment figure in early development is a dimen-
sion not fully captured by either deprivation or threat. Rather, we
propose that these are two dimensions of experience that have not
previously been clearly differentiated or explained by prevailing
models focused on stress pathways and argue that these dimen-
sions of experience exert strong and distinct influences on neural
development.
1. Distinguishing between deprivation and threat
The framework we propose here distinguishes between core
dimensions of environmental experience that underlie different
forms of childhood adversity and describes their distinct impacts
on neural development. The central distinction we make is between
experiences of deprivation and experiences of threat. We sug-
gest that these dimensions of experience can be assessed across
different forms of childhood adversity (e.g., physical and sex-
ual abuse, domestic violence, institutionalization, neglect) and
will differentially predict aspects of neurodevelopment and ulti-
mately behavior. Experiences of deprivation involve the absence
of expected cognitive and social inputs as well as the absence
of species- and age-typical complexity in environmental stimuli.
The impact of low environmental complexity on cortical develop-
ment has been well studied in animal models of sensory and global
deprivation and is conserved across species (Diamond et al., 1972;
Leporé et al., 2010; O’Kusky, 1985). The dimension of deprivation
is central for children exposed to institutionalization, neglect, and
poverty (Fig. 1). In contrast, experiences of threat include events
that involve actual or threatened death, serious injury, sexual vio-
lation, or other harm to one’s physical integrity. Threat experiences
are conceptually similar to events defined as traumatic in the
Diagnostic and Statistical Manual of Mental Disorders (American
Psychiatric Association, 2013). Events involving threat of serious
harm result in strong learning mediated by emotional learning
networks that have been well characterized in animals and are
conserved across species (Johansen et al., 2011; LeDoux, 2003).
Threat is a primary dimension of experience for children exposed
to physical and sexual abuse, domestic violence, and other types
of interpersonal violence (Fig. 1). Critically, we do not propose
that exposure to deprivation and threat experiences occurs inde-
pendently for children, as most of the exposures described above
co-occur. Instead we propose that they can be measured separately
and have unique effects on neurodevelopment.
Below we separately describe deprivation and threat and
their distinct impact on neural structure and function. Within
each section we first review mechanisms of neural development
from animal neuroscience (see Table 1 for a summary of animal
paradigms included), describe how neuroimaging and neuropsy-
chological measures in humans may reflect these processes, and
review how exposure to deprivation and threat may shape these
aspects of neural development in light of evidence from animal
studies and emerging human research. Throughout we identify
plausible mechanisms through which commonly studied forms of
adversity (e.g., maltreatment, institutionalization) may come to
affect neural development, leading to our novel model of envi-
ronmental experience. We end by proposing directions for future
research into the impact of adversity on neural development that
will confirm or disprove these hypothesized pathways.
2. Deprivation
2.1. Predictions based on animal literature
One of the areas where the impact of experience on neural devel-
opment has been most clearly documented is in the pruning of
synaptic connections during development in the central nervous
system. These principals were first examined in studies employing
sensory deprivation (Wiesel and Hubel, 1965b). Studies of deprived
or anomalous sensory input during development illustrated that
one of the primary mechanisms through which early experi-
ence shapes neural structure and function is by pruning initially
over-produced synaptic connections (Huttenlocher et al., 1982),
described more than three decades ago as the selective-elimination
hypothesis (Changeux and Danchin, 1976; Petanjek et al., 2011;
Purves and Lichtman, 1980). Here we propose that the same mech-
anisms through which sensory deprivation or anomalous sensory
environments shape primary sensory cortex in animals may also
be the mechanism through which broader social-cognitive depriva-
tion shapes association cortex in humans. We argue that we can use
basic principals of sensory deprivation to make predictions about
the way that decreased exposure to cognitive and social stimula-
tion affects neural development. Specifically, we suggest that an
early environment without cognitive enrichment will yield a neu-
ral structure designed to deal with low complexity environments.
We predict that exposure to cognitive and social deprivation in
children results in (a) age-specific reductions in thickness and vol-
ume of association cortex, as measured in vivo using MRI, due in
part to early or over-pruning of synaptic connections, lower num-
bers of synaptic connections, and reduced dendritic branching;
and (b) reduced performance on tasks that depend on these areas
(e.g., complex cognitive tasks). We expect that reductions in corti-
cal thickness should be most pronounced in regions of association
cortex that are recruited for processing complex social and cogni-
tive inputs, including prefrontal cortex (PFC), superior and inferior
parietal cortex, and superior temporal cortex.
We limit our argument to the development of association cortex
simply because association cortex has a prolonged developmental
trajectory relative to most areas of primary sensory cortex (Gogtay
et al., 2004; Huttenlocher, 1979) and because social and cognitive
inputs likely shape areas of cortex involved in complex social and
cognitive processing. The term association cortex refers to lateral
and medial prefrontal, parietal, and temporal areas of cortex that
are not primarily involved in processing sensory stimuli or motoric
responding but instead are activated in response stimuli that
require cognitive processing (Goldman-Rakic, 1988; Mountcastle
et al., 1975). These regions are considered amodal in that they
respond to and process stimuli across multiple sensory modalities.
While association cortex is likely to be organized along governing
principals (Badre and D’Esposito, 2009), these principals continue
to be investigated and are thought to be different to the organi-
zational principals of primary sensory cortex (e.g., retinotopy).
Generally it is understood that association cortex is necessary
for higher-level cognitive processes such as executive function,
language, and spatial navigation as well as social cognition. We
acknowledge that association cortex refers to a large area of cortex,
 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591 581

Fig. 1. Dimensions of threat and deprivation associated with commonly occurring adverse childhood experiences (ACEs). Importantly, we argue that threat and deprivation are
dimensions of experience that can be measured among children exposed to a wide ranges of ACEs, both those that occur in isolation (e.g., a single incident of community
violence exposure) and those that are co-occurring (e.g., physical abuse and physical neglect). We use the term complex exposures to refer to experiences that in most cases
involve aspects of both threat and deprivation. Institutionalization is one such exposure, which involves deprivation in both cognitive and social inputs – consistent with our
definition of deprivation – as well as the absence of a primary attachment figure, which is an atypical experience that can represent a significant threat to safety and survival
for an infant in the extreme absence of care. Note that institutional rearing also involves lack of species-typical expectations of the presence of an attachment figure in early
development (Tottenham, 2012), a dimension not fully captured by either deprivation and threat. Poverty differs in fundamental ways from the other exposures we describe.
Critically, poverty does not inherently involve dimensions of either threat or deprivation (i.e., it is possible to be poor and to have no exposure to threatening experiences and
typical exposure to cognitive, social, and environmental complexity). However, poverty is often a marker of exposure to both threat and deprivation, particularly deprivation
in exposure to enriching and cognitively complex environments. Because the degree of threat and deprivation exposure associated with poverty is heterogeneous, this could
be one reason that the findings with regard to poverty and neural development have been inconsistent across studies. Figure reproduced, with permission, from Sheridan
and McLaughlin (2014).

making our predictions relatively non-specific. However, greater
specificity in these predictions requires improvements in our
measurement of deprivation in both animal and human models,
and greater understanding of the specific types of social and
cognitive inputs that are required for diverse regions of association
cortex to develop normally. As we review below, the hypothesis
that exposure to deprivation preferentially affects association
cortex is born out in the current data on the association between
exposure to environments characterized by deprivation and neural
structure and function in humans.
2.1.1. Proliferation and pruning
Early in the study of neural structure, it was hypothesized
that synaptic connections emerged following a genetic blue print

Table 1
Dimensions of deprivation and threat associated with commonly used animal paradigms of early adversity.

Paradigm Description Primary dimension

Dark Rearing Animals that typically develop ocular dominance columns (e.g., cats) are deprived of visual Deprivation
input via rearing in complete darkness. Animals are not deprived of other forms of sensory
input (sound, tactile, taste, smell) but are raised without visual input until they are
post-pubertal
Individual rearing Rodents are single-housed after weaning to reduce visual, auditory, and olfactory Deprivation
communication and to prevent physical interactions with littermates housed in separate
cages in the same room
Repetitive foot shock1 Rodents are exposed to a series of aversive foot shocks in a closed chamber. The series of Threat
shocks is repeated daily for a number of consecutive days.
Chronic restraint Rodents are physically restrained for a specified number of hours. Restraint is repeated Threat
daily for a number of consecutive days.
Predator odor Rodents are exposed to a natural predator odor in a closed chamber for a specified number Threat
of hours. Exposure is repeated daily for a number of consecutive days
Minimal bedding Rodent dam and litter are housed with a minimal amount of nesting and bedding Threat
materials for a specified number of days prior to weaning. Minimal bedding is associated
with rough handling of and stepping on pups as well as inconsistent and fragmented
dam-pup interactions (Raineki et al., 2012)
Chronic maternal separation Litter is removed from rodent dam and placed in an incubator for a specified number of Deprivation and Threat
hours. Separation is repeated daily for a number of consecutive days prior to weaning
1
Foot shock is the most commonly used stimulus in fear conditioning rodent models, which can also be used as models of early adversity (Raineki et al., 2010; Raineki
et al., 2012; Sarro et al., 2014; Sevelinges et al., 2011).
582 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
(Sperry, 1963). However, the “preformist” theory rapidly gave
way to evidence in favor of the selective-elimination hypothe-
sis that emphasized the critical role that environmental inputs
played in shaping neural structure (Changeux and Danchin, 1976).
Since that time, decades of work have documented that central
and peripheral nervous system development contains two distinct
phases of synaptic growth, which ultimately shape adult neural
structure and function: proliferation and pruning. Synaptic prolif-
eration occurs in a period beginning during the third trimester,
peaking about three months after birth, and ending before the
second year of life (Huttenlocher and Dabholkar, 1997; Petanjek
et al., 2011). During this period, there are rapid increases in the
ratio of asymmetrical to symmetrical synapses (an index of newly
formed synaptic connections), synaptic density, and total number
of synapses (Huttenlocher and de Courten, 1987; Rakic et al., 1986).
Following synaptic proliferation, a period of pruning of synaptic
connections occurs and continues for an extended period through
childhood and adolescence. In humans, this synaptic elimination
occurs earlier for primary sensory cortex and later for association
cortex, although the final density of synapses in adulthood across
areas of cortex is not different (Huttenlocher, 1979; Huttenlocher
and Dabholkar, 1997; Huttenlocher and de Courten, 1987).
Pruning of synaptic connections occurs in all six layers of cor-
tex, but occurs primarily for synaptic connections on dendritic
spines as compared to other classes of synapses on dendritic shafts
or cell somas (Rakic et al., 1986). This is likely a corollary of the
finding that presynaptic neurons rely on trophic factors released
from their post-synaptic targets, and thus co-activation, for sur-
vival (Purves and Lichtman, 1980). That is, as two cells co-activate,
the association between the cells strengthens, trophic factors are
transmitted, and it becomes more likely that this synaptic connec-
tion will survive. In contrast, if a synaptic connection is infrequently
activated, this connection becomes weaker over time and is likely to
be pruned. Conceptually, the emergent system reflects the relative
effectiveness of various pathways, theoretically yielding the most
efficient system where only the most effective and environmen-
tally relevant connections remain. Thus, through the interaction of
pre and post-synaptic cell interactions, the elimination of synapses
during development gives rise to the adult organization of the
peripheral and central nervous system.
2.1.2. Visual deprivation as early experience
Much of the early work concerning the effect of experience on
neural structure and function comes from investigations of the
effect of visual deprivation on visual cortex structure and function.
In animals this has been observed through experimental manip-
ulation of visual input during development. In initial studies of
monocular deprivation, kittens were deprived of visual input to
one eye during development, leading to irreversible changes in
ocular dominance columns. In contrast, monocular deprivation in
adult cats leads to no such irreversible effects (Wiesel and Hubel,
1965a,b). Importantly, where early monocular deprivation leads
to changes in visual cortex organization, complete visual depri-
vation, or “dark rearing” leads to radical reductions in synapses
in primary visual cortex (V1) and irreversible decreases in visual
acuity (O’Kusky, 1985). These and other findings ultimately led to
the concept of developmental plasticity: the understanding that
early experience has a preferentially permanent impact on neu-
ral structure, in particular during specific periods termed sensitive
or critical periods when environmental stimuli have a more pro-
nounced impact on neural structure and function (Hensch, 2005;
Morishita and Hensch, 2008; O’Kusky, 1985).
In humans, the impact of sensory deprivation on neural develop-
ment has been studied in individuals with congenital and late-onset
blindness. Congenital blindness is associated with increased use
of visual cortex to process auditory stimuli and the spatial
relationships between auditory stimuli (Voss et al., 2008). In addi-
tion, congenitally blind individuals activate these cortical areas
during tasks requiring the processing of auditory or tactile stimuli
and when performing complex cognitive tasks (Collignon et al.,
2013). This pattern of re-organization appears to reflect the fact
that congenitally blind individuals may be able to use the inherent
organizational structure of extrastriate cortex to process complex
perceptual stimuli in other sensory modalities. Moreover, congeni-
tally blind individuals have thinner primary visual cortex compared
to sighted or late-blind participants (Collignon et al., 2013; Leporé
et al., 2010), indicating that the reduction of inputs into primary
visual cortex results in reductions in cortex and thus reduced
processing capacity.
Thus it appears in humans and rodents that, (a) reduction in
sensory inputs during periods of developmental plasticity leads
to thinner cortex in primary sensory areas, due at least in part
to increased synaptic pruning; and (b) non-primary sensory areas,
such as extra-striate cortex, can be ‘colonized’ by other sensory and
cognitive processes when typical inputs are absent. In humans, this
appears to result in more diffuse patterns of activation in response
to task demands. However, even in the context of cortical ‘colo-
nization’, cortical thinning occurs within primary sensory areas,
indicating that the synaptic connections associated with reduced or
absent environmental input may be observable using neuroimag-
ing techniques.
2.1.3. Global deprivation in animal models
A second literature in rodents has investigated the impact of a
more general developmental experience, that of global deprivation
and enrichment. It has been amply demonstrated in animal mod-
els that global deprivation due to single rodent housing results in
widespread decreases in dendritic arborization, spines, and over-
all brain volume (Bennett et al., 1996, 1974; Diamond et al., 1966,
1972; Globus et al., 1973). This change in cortical structure has
been observed following random assignment to individual housing
with decreased visual, auditory, and social inputs for pre-pubertal
and peri-pubertal animals (Bennett et al., 1996). Changes in den-
dritic morphology are marked throughout cortex (Diamond et al.,
1975), are stronger and more persistent if the duration of expo-
sure is longer (Bennett et al., 1974), and decline slowly following
a transition to a new environment. These changes appear to be
at least partially reversible through exposure to enriching, cogni-
tively stimulating environments following deprivation (Diamond
et al., 1972). Because the current evidence from rodent models of
deprivation and enrichment are not tied specifically to the devel-
opmental stage at which exposures occur, it is difficult to know
if such exposures would have a larger and less malleable impact
if they occurred earlier or if they would have a smaller and more
reversible impact if they occurred later.
In sum, evidence from the animal literature indicates that
decreases in environmental input within a single modality (e.g.,
vision) during development can disrupt cortical organization and
decrease dendritic arborization and number of synapses within
corresponding sensory cortex regions. In animals exposed to multi-
faceted deprivation, a general lack of stimulation, general decreases
in cortical thickness are observed due to decreases in dendritic
arborization, neuronal depth, and glia cells. An obvious next step
is to determine whether similar patterns of neural outcome are
observed in children exposed to social and cognitive deprivation.
2.2. Consistency with evidence from human studies
We next review evidence from studies of children exposed
to diverse environments that share the characteristic of lacking
complexity in social and cognitive inputs. These include institu-
tionalization, low socio-economic status (SES), and neglect, each of
 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
which are characterized by deprivation in social stimulation, cog-
nitive inputs (e.g., language), and in the case of institutionalization,
the absence of a primary attachment figure (Hart and Risley, 1995;
Hildyard and Wolfe, 2002; Smyke et al., 2007). Given observed neu-
ral changes following sensory and global deprivation in rodents, it
is likely that these forms of social and cognitive deprivation will
result in changes in thickness and volume in humans, as mea-
sured using MRI. We predict that exposure to these diverse forms
of deprivation will be associated with age-specific reductions in
cortical thickness as a result of decreases in dendritic arboriza-
tion, spines, and density. Moreover, we expect that reductions in
cortical thickness will be most pronounced in regions of associ-
ation cortex that are recruited for processing complex social and
cognitive inputs, including the PFC, superior parietal cortex, and
superior temporal cortex. As shown below, existing evidence sup-
ports these predictions. Critically, however, because fine-grained
measurement of the dimensions of deprivation and threat have
not typically been undertaken in human studies of neurodevel-
opment and because prior studies have often focused on specific
types of exposure (e.g., abuse) without measuring or reporting co-
occurring exposures (e.g., neglect), any conclusions regarding the
consistency of existing human work with our proposed framework
are necessarily tentative.
Institutionalization in early childhood is a well-studied
phenomenon involving exposure to profoundly deprived envi-
ronments in early childhood. This exposure is complex and
heterogeneous. However, most children in institutions are clearly
deprived of species-expectant early experiences of two types. First,
both the ratio of caregivers-to-children and caregiver investment
in children are low (McCall et al., 2012; Zeanah et al., 2003).
This lack of an early attachment figure, a central feature of early
human experience, has been investigated and reviewed exten-
sively by Tottenham and colleagues (Gee et al., 2013; Tottenham,
2012; Tottenham et al., 2010), and as such we do not review these
effects in depth. However, briefly, lack of an early attachment figure
results in increased susceptibility to anxiety that appear to be medi-
ated by changes in amygdala structure and function (Tottenham,
2012). These findings are consistent with animal studies investigat-
ing deprivation of early maternal care (Eiland and McEwen, 2012;
Tottenham and Sheridan, 2009).
Second, institutional rearing is associated with decreased social
and cognitive inputs of numerous kinds. Children raised in institu-
tions are less likely than children raised in families to be exposed
to all forms of language, interactions with adults, variation in daily
routines and experiences, novel and age-appropriate enriching cog-
nitive stimuli (e.g., books, toys), opportunities for peer interaction,
and a wide range of other types of environmental stimulation
(Nelson et al., 2009; Smyke et al., 2007; Zeanah et al., 2003).
Likely as a result of this profound social and cognitive depriva-
tion, children raised in institutions are more likely than children
raised in families to have deficits in cognitive function (Nelson
et al., 2007; O’Connor et al., 2000) and in language production and
comprehension (Albers et al., 1997; Windsor et al., 2011). Relat-
edly, children reared in institutional settings have a wide range
of developmental problems including markedly elevated rates of
attention-deficit/hyperactivity disorder (ADHD) (Kreppner et al.,
2001; Zeanah et al., 2009). Several recent studies document associ-
ations between institutionalization and grey matter volume and
thickness. In addition to being associated with global changes
in cortical function (Chugani et al., 2001; Marshall et al., 2008;
McLaughlin et al., 2010), institutionalization is associated with
overall decreases in grey matter volume and thickness (McLaughlin
et al., 2014; Mehta et al., 2009; Sheridan et al., 2012a), with the
most pronounced reductions in areas of association cortex sup-
porting complex cognitive and social processing including the PFC,
superior and inferior parietal cortex, and superior temporal cortex
583
(McLaughlin et al., 2014). In some areas of cortex these decreases
in thickness mediate the association between institutionali-
zation and atypical cognition function (e.g., ADHD symptoms;
McLaughlin et al., 2014).
Although low parental SES is not as clear-cut or extreme an
exposure as institutionalization, it similarly confers risk for less
complex cognitive inputs during childhood. Low parental SES is
associated with decreased complexity and amount of linguistic
inputs (Hart and Risley, 1995), lower exposure to enriching cogni-
tive experiences in the home (Bradley et al., 2001a,b) and in the
school environment (Sirin, 2005), including decreased access to
books and extracurricular experiences. Unsurprisingly, given this
difference in exposure to complex cognitive stimuli, low SES is asso-
ciated with decreased performance on complex cognitive tasks,
including those tapping executive function and long-term memory
(Evans and Schamberg, 2009; Farah et al., 2006; Hackman et al.,
2010; Kishiyama et al., 2009; Noble et al., 2007), language abil-
ity (Fernald et al., 2013; Weisleder and Fernald, 2013), and overall
cognitive and academic achievement (Brooks-Gunn and Duncan,
1997; Duncan et al., 1998; Jokela et al., 2009; Sirin, 2005). These
differences in developmental outcomes are mediated by lack of
exposure to complex and enriching activities in childhood (Bradley
et al., 2001a,b; Linver et al., 2002; Yeung et al., 2002). In addition
to the well-documented associations between low SES and cog-
nitive function, low SES is additionally associated with decreased
volume and volume by age in association cortex, particularly the
PFC (Noble et al., 2012; Sheridan et al., in prep). Additionally, low
SES is associated with increased levels and more diffuse patterns
of activation in association cortex to support performance on lan-
guage and executive functioning tasks in both children (Raizada and
Kishiyama, 2010; Raizada et al., 2008; Sheridan et al., 2012b) and
adults (Gianaros et al., 2008; Gianaros and Manuck, 2010; Gianaros
et al., 2011). Further, in at least one instance the impact of low
SES on neural function was explained by lack exposure to complex
cognitive experiences, including language (Sheridan et al., 2012b).
Neglect refers to inadequate care on the part of parents for their
offspring. This can include a lack of provision for basic needs such
as food, shelter, and clothing or a lack of provision for the emo-
tional needs of a child. Because neglect inherently involves a lack
of parental care, it constitutes an obvious form of early depriva-
tion. When neglect is directly compared to abuse, children exposed
to neglect are at greater risk for cognitive deficits than children
exposed to abuse (Hildyard and Wolfe, 2002) and these deficits
are similar to those observed in severe poverty and institutionali-
zation (Dubowitz et al., 2002; Spratt et al., 2012), consistent with
our conceptualization of neglect as a form of deprivation. Moreover,
childhood emotional neglect predicts poor performance on a cog-
nitive control task and a more widespread pattern of dorsolateral
PFC activation during trials requiring inhibitory control (Mueller
et al., 2010).
3. Threat
3.1. Predictions based on animal literature
Evidence from animal and human studies demonstrates consis-
tently that early exposure to threat is associated with long-term
changes in neural circuits that underlie emotional learning. Based
on this evidence, we argue that early threat exposure impacts the
structure, function, and coupling of the hippocampus, amygdala,
and ventromedial prefrontal cortex (vmPFC). First, we predict that
early threat exposure leads to changes in hippocampal morphology
and function, including reduced dendritic spines and arboriza-
tion and poor function in hippocampus-dependent learning and
memory tasks. These predictions are based on extensive evidence
584 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
that potential threats activate the hypothalamic–pituitary–adrenal
(HPA) axis, leading to enhanced expression of corticotropin
releasing hormone (CRH) in the hippocampus and damage to hip-
pocampal neurons (Brunson et al., 2001; Ivy et al., 2010).
Second, we argue that early exposure to threat leads to changes
in amygdala function. The amygdala detects and processes salient
environmental stimuli, particularly stimuli that have emotional
significance, such as facial displays of emotion (Adolphs, 2010;
Davis and Whalen, 2001; Fitzgerald et al., 2006; Liberzon et al.,
2003). Although the amygdala responds to both positive and
negative emotional stimuli (Somerville et al., 2004), evidence
suggests that it is centrally involved in detection of potential
threats (Isenberg et al., 1999; Ohman, 2005) and required for the
acquisition and expression of learned fear (Johansen et al., 2011;
LeDoux, 2003). We suggest that early threat exposure leads to
novel learning, resulting in the pairing of threat cues with pre-
vious neutral stimuli, a reduced threshold for experiencing fear,
and heightened vigilance to detect other potential threats (van
Marle et al., 2009), all of which are adaptive responses to poten-
tial danger. Together, these changes result in elevated amygdala
activation to emotional stimuli due to the increased salience of
such information, and potentially as a result of up-regulation of
CRH receptors in the amygdala (Hatalski et al., 1998). Behaviorally,
this results in heightened attention to threat-related cues, gener-
alization of learned fear to previously neutral stimuli, and elevated
emotional responses to a wide range of emotional cues. For a
review of how institutionalization, a specific form of childhood
adversity associated with high degrees of both threat and depri-
vation, influences amygdala development, please see Tottenham
(2012).
Finally, we propose that chronic experiences of threat have addi-
tional influences on neural systems involved in modulating the
amygdala and hippocampus. As a result of fear extinction mecha-
nisms, exposure to consistently safe environments following early
threats will result in new learning that inhibits previously acquired
fear responses to threatening cues, termed extinction learning.
The vmPFC is activated during retrieval of extinction learning and
down-regulates the amygdala (Milad and Quirk, 2012; Milad et al.,
2007; Quirk et al., 2003; Quirk et al., 2000). The vmPFC is thus essen-
tial for retention of extinction learning and inhibition of fear (Phelps
et al., 2004; Quirk et al., 2000). However, learned fear continues to
be represented in the amygdala and hippocampus, and previously
extinguished fear can be re-activated following exposure to situa-
tions where fear learning initially occurred or to other threatening
contexts (Bouton, 2002; Bouton et al., 2006; Rescorla, 2004). As
such, we predict that chronic threat exposure will result in stronger
representations of conditioned fear than extinction memories, low-
ering recruitment of the vmPFC in multiple forms of emotional
processing. Over time, this reduced vmPFC recruitment will lead
to accelerated pruning, resulting in reduced vmPFC thickness, and
poor vmPFC-amygdala coupling (i.e., low structural and functional
connectivity between these regions).
To justify our predictions regarding early threat and emotional
learning networks, we review evidence from the animal litera-
ture on mechanisms underlying fear learning and extinction given
substantial existing knowledge of the neural circuitry underly-
ing these mechanisms and the consistency of that circuitry across
species. Importantly, some (i.e., effects on hippocampus), but not
all (i.e., effects on vmPFC), of the predictions outlined above have
previously been articulated within the literature on stress and
neural development (Tottenham and Sheridan, 2009). Indeed, the
pathways we describe with regard to the hippocampus and amyg-
dala have frequently been invoked as mechanisms through which
stress influences the brain. We review this literature nonetheless
as we expand upon prior predictions, identify other mechanisms
(i.e., fear learning) that might alter hippocampus and amygdala
development following threatening or traumatic experiences, and
highlight the distinction between neural systems influenced by
threat as compared to deprivation.
3.1.1. Fear learning
Fear is a defensive mechanism that activates behavioral and
neurobiological responses to danger that promote survival, includ-
ing freezing and activation of sympathetic nervous system and
HPA axis, generating downstream hormonal and metabolic changes
(LeDoux, 2003). An extensive literature in rodents has charac-
terized the neural circuitry that underlies fear learning using
Pavlovian fear conditioning tasks (Johansen et al., 2011; Kim and
Jung, 2006; LeDoux, 2003). In Pavlovian conditioning a previ-
ously innocuous stimulus (conditioned stimulus, CS) is paired
with an aversive or threatening unconditioned stimulus (US). After
repeated contingent pairings, the CS begins to elicit the behavioral
and neurobiological responses associated with the US. Fear condi-
tioning happens without effort, allowing threats to quickly elicit
defensive responses that promote safety. In the animal literature,
the amygdala and hippocampus contribute differentially to aspects
of fear learning. The amygdala is necessary for both the acquisi-
tion and expression of conditioned fear in paradigms involving a
cued CS (i.e., a simple sensory stimulus, like a tone or light) and
a contextual CS (i.e., a more complex polymodal stimulus, such
as the place where cue conditioning occurs; (Phillips and LeDoux,
1992). In contrast, the hippocampus is involved only in the acquisi-
tion of conditioned fear to complex contextual stimuli (Phillips and
LeDoux, 1992). Lesions of the amygdala prevent fear acquisition
and expression to both cued and contextual CS, while hippocampal
lesions prevent fear acquisition only to contextual CS (Anagnostars
et al., 1999; Cousens and Otto, 1998; Hitchcock and Davis, 1986;
Phillips and LeDoux, 1994).
Learned fear is not immutable; conditioned fear generally abates
with the passage of time as a result of extinction processes. Exten-
sive evidence suggests that fear extinction involves novel learning
of an association between the CS and absence of the US, rather than
a loss of the initial CS-US association (Quirk, 2002). Because the CS-
US pairing remains intact, extinguished fear can be re-activated
through a variety of processes, including spontaneous recovery,
exposure to novel threats, exposure to the CS in novel contexts, or
re-exposure to the US, highlighting the context-dependent nature
of extinction learning (Bouton, 2002, 2004; Bouton and King, 1983;
Rescorla, 2004). Extinction of conditioned fear initially requires the
amygdala, whereas retrieval of extinction memory on subsequent
days additionally requires the vmPFC (Falls et al., 1992; Morgan
et al., 1993; Quirk et al., 2000), which has direct projections to
the amygdala (Hurley et al., 1991). vmPFC activation during recall
of extinction memory inhibits the amygdala and dampens fear
expression (Knapska and Maren, 2009; Milad and Quirk, 2002).
Thus, successful fear extinction requires functional coupling of the
vmPFC and amygdala (Quirk et al., 2003).
3.1.2. Effects of early threat on fear learning circuits
Exposure to threatening stimuli early in development has con-
sistently been shown to alter the neural circuitry underlying fear
conditioning and extinction. Here we focus on paradigms that
specifically elicit fear, including repeated foot shock, physical stress
(e.g., restraint), and predator odor (see Table 1). We also highlight
findings from minimal bedding paradigms that result in erratic,
inconsistent maternal care provided to pups (Rice et al., 2008), as
well as increases in rough handling of pups by the dam (Raineki
et al., 2012; Roth and Sullivan, 2005). In the service of focusing
explicitly on models of threat, we do not review paradigms that
elicit more complex emotional and neural responses, including
early maternal separation (Liu et al., 1997), which involves both
high threat as well as high degrees of deprivation resulting from
 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
isolation and lack of both social and cognitive inputs during sepa-
ration.
An extensive literature documents that acute and uncontrol-
lable stressors in adulthood result in reduced dendritic length and
branching as well as lower plasticity and long-term potentiation
in the hippocampus, and impairments in hippocampus-dependent
learning and memory (Kim et al., 2006; McEwen, 1999). Early threat
exposure results in similar shifts in adult hippocampal structure
and function in studies using a wide range of paradigms. Chronic
restraint stress during pre-adolescence is associated with reduced
apical dendritic length and branching of pyramidal neurons in the
hippocampus and mPFC (Eiland et al., 2012). Dendritic atrophy,
reduced long-term potentiation in the hippocampus, and deficits
in hippocampus-dependent learning and memory have also been
observed in adult rats following early exposure to minimal bed-
ding (Brunson et al., 2005; Ivy et al., 2010; Rice et al., 2008).
Notably, some evidence suggests that the effects of early threat
exposure on hippocampal morphology and cellular function do
not emerge until adulthood (Isgor et al., 2004; Tsoory et al., 2008)
and the effects of threat on hippocampal function appear to be
larger when exposure occurs in childhood as compared to adult-
hood (Chen et al., 2006). Early threat exposure also appears to
influence hippocampus-dependent aspects of fear conditioning.
For example, in multiple studies, early exposure to repeated foot
shock stress predicts attenuated extinction of fear-related freez-
ing behavior during exposure to a contextual CS in adulthood, but
no differences in the response to initial conditioning (Ishikawa
et al., 2012; Matsumoto et al., 2008). Similarly, impaired extinction
recall of context-dependent fear extinction following early threat
results from disruptions in signaling in the vmPFC-hippocampus
circuit, including poor synaptic transmission between these regions
(Toledo-Rodriguez and Sandi, 2007). Multiple studies have found
that the effects of early threat experiences on hippocampal devel-
opment are mediated by excess levels of CRH and activation of
CRH receptors in the hippocampus (Brunson et al., 2001; Ivy et al.,
2010). These effects have sometimes been found to vary by sex. For
example, exposure to predator odor followed by placement on an
elevated platform in pre-adolescence is associated with impaired
contextual learning in females during adolescence, as evidenced
by reduced freezing to a contextual CS. In contrast, males exhibit
enhanced fear conditioning to a cued CS in adolescence and reduced
extinction to the cued CS in adulthood following this exposure
(Toledo-Rodriguez and Sandi, 2007).
Early exposure to threatening stimuli also leads to long-
term changes in the structure and function of the amygdala.
In paradigms involving uncontrollable shock delivered to pups,
early threat exposure is associated with persistent anxiety and
depression-like behaviors, absence of paired-pulse inhibition in
the amygdala—reflecting deficits in inhibitory pathways regulat-
ing amygdala activity, and widespread changes in gene expression
in the amygdala, particularly in genes that regulate serotonin and
GABA (Sarro et al., 2014; Sevelinges et al., 2011). In addition,
chronic threat exposure leads to increased expression of CRH mRNA
in the amygdala, potentially lowering the threshold for the expres-
sion of fear (Hatalski et al., 1998). Pre-adolescent chronic restraint
stress is associated with atypical dendritic morphology, includ-
ing increased spines, in the amygdala (Eiland et al., 2012). Similar
effects on the amygdala have been observed in rodents exposed to
the maternal minimal bedding paradigm. These include persistent
elevations in c-Fos expression in the amygdala that increase with
development (Cohen et al., 2013) and elevated amygdala activity
to a forced swim test in adolescence that mediates depression-like
responses to the stressor (Raineki et al., 2012).
Taken together, the rodent literature suggests that early expo-
sure to uncontrollable threat results in long-term changes in
hippocampal and amygdala structure and function as well as
585
deficits in inhibitory control of these regions by the mPFC. Specif-
ically, early threat predicts, (a) reduced dendritic length and
arborization in the hippocampus in adulthood, (b) dampened long-
term potentiation in the hippocampus, (c) poor performance on
hippocampus-dependent learning and memory tasks, (d) increased
dendritic length in the amygdala; (e) elevations in basal amyg-
dala activity as well as amygdala response to novelty and stress,
(f) increased anxiety and depression-like behaviors mediated by
amygdala over-activity; and (g) deficits in the functional coupling
of the mPFC with the hippocampus and amygdala, as evidenced
by reduced synaptic transmission between these regions and poor
recall of extinction learning.
3.2. Consistency with human studies
The learning mechanisms and neural circuitry underlying fear
conditioning and extinction are highly conserved across species.
As in the animal model, amygdala activation is associated with fear
acquisition and expression during conditioning (LaBar et al., 1998;
Phelps et al., 2004). Likewise, the vmPFC is activated during extinc-
tion recall (Milad et al., 2007; Phelps et al., 2004), and increased
vmPFC activity during such recall is associated with dampened
amygdala activity (Milad et al., 2007, 2009; Milad and Quirk, 2012).
The vmPFC is thus essential for retention of extinction learning and
plays a central role in modulating the amygdala. Because acquiring
neuroimaging data requires participants to be in a highly salient
and novel context, the role of the hippocampus in contextual fear
conditioning has been difficult to study in humans.
Despite the consistency with which fear learning mechanisms
have been specified across animal and human models, there is a
surprising lack of human research on how exposure to early expe-
riences of threat influences fear conditioning across development.
Although numerous studies have examined fear conditioning pro-
cesses in adults with post-traumatic stress disorder (Orr et al.,
2000; Peri et al., 2000), research on early threat exposure and
fear learning in youths or adults is absent in the current litera-
ture. One of the challenges is developing paradigms that can be
used ethically in children and adolescents, given that effective
adult fear conditioning paradigms utilize shock as the US (Pine
et al., 2001). A recently-developed task pairing emotional faces
with a human scream as the US holds promise in this regard (Lau
et al., 2011), but has yet to be applied to the study of early threat
exposure. We review existing human studies examining associ-
ations between early threat and structure and function of the
hippocampus, amygdala, and vmPFC, although we note that direct
comparisons between animal and humans studies should be made
with caution given the lack of studies examining early threat and
fear learning in humans.
Based on the animal literature, we predict that early threat
exposure leads to parallel changes in the structure and function
of the hippocampus, amygdala, and vmPFC observed in animals.
We review evidence for these predictions from studies of chil-
dren exposed to threatening environments, including physical and
sexual abuse, domestic violence, and other types of interpersonal
violence. These environments share the characteristic of being
significant threats to survival and therefore activate the neural
circuitry underlying fear learning. Importantly, as noted above,
because of the high co-occurrence of threat and deprivation expo-
sure and because few studies have examined both dimensions
within the same sample of children, the specificity of these effects
remains to be confirmed in future studies.
Although early threat exposure has consistently been associ-
ated with reduced hippocampal volume in adults (Andersen and
Teicher, 2008; Hart and Rubia, 2012; Teicher et al., 2012), studies
of children have generally not found a relationship between threat
exposure and hippocampal volume (De Bellis et al., 2001; Woon
586 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
and Hedges, 2008). This pattern has led some to suggest that the
effects of early threat on hippocampal development are not evi-
dent until adulthood (Tottenham and Sheridan, 2009), consistent
with evidence from animal studies (Isgor et al., 2004), although the
exact mechanisms explaining this developmental pattern remain
to be identified. Atypical hippocampal function associated with
early threat has been observed, however. For example, children
with maltreatment-related PTSD symptoms exhibit less hippocam-
pal activation during retrieval in a verbal declarative memory task
than non-maltreated children (Carrion et al., 2010).
Differences in the volume of the amygdala as a function of threat
exposure have generally not been found in children (De Bellis et al.,
2001). However, atypical processing of emotional information –
particularly facial emotion – has been observed consistently. Chil-
dren exposed to threat exhibit amplified neural response to angry
faces in ERP studies (Pollak et al., 1997, 2001), and heightened
amygdala activation to angry faces (McCrory et al., 2011) even when
faces are presented pre-attentively (McCrory et al., 2013). These
alterations in neural processing of facial emotion are consistent
with behavioral findings suggesting that children with early threat
exposure identify facial displays of anger more quickly and with less
sensory information than non-exposed children (Pollak and Sinha,
2002), suggesting attention biases that facilitate the identification
of anger.
Consistent with animal literature demonstrating differences
in the development of the vmPFC following early threat, multi-
ple recent studies observe that threat exposure in childhood is
associated with reduced volume and/or thickness of the vmPFC
(De Brito et al., 2013; Edmiston et al., 2010; Hanson et al.,
2010; Kelly et al., 2013), consistent with our prediction that low
recruitment of vmPFC will lead to accelerated pruning in this
region. In addition, a recent study documents reduced resting-state
amygdala-vmPFC connectivity in adolescent females exposed to
child abuse (Herringa et al., 2013).
4. Recommendations for future research
The exposures that give rise to experiences of deprivation and
threat co-occur at high rates in children and adolescents (Green
et al., 2010; McLaughlin et al., 2012). This co-occurrence has gen-
erated many of the methodological and conceptual challenges in
identifying dimensions of experience that influence specific aspects
of neural development. We do not advocate that future research
attempt to identify children who experience only one specific form
of adversity, as that would surely result in conclusions that are not
generalizable to most children exposed to adverse developmental
environments. Instead, we propose the following concrete recom-
mendations for future research. First, future studies examining
neural development in children exposed to adverse early environ-
ments should measure the underlying dimensions of experience
described here in addition to the traditional categories of expo-
sure (e.g., physical and sexual abuse, neglect, poverty) to determine
whether deprivation and threat are indeed associated with the pre-
dicted patterns of neural development proposed here. Dimensional
measures of trauma exposure frequency and severity are widely
available (Bernstein et al., 2003), and measures of environmental
enrichment have been developed for young children (Caldwell and
Bradley, 1984). Developing more extensive measures of social and
cognitive inputs and environmental complexity that can be used
over a wider range of development would facilitate this endeavor.
Relatedly, a second central challenge in characterizing the
impact of deprivation on neural development involves determining
the specific types of social and cognitive inputs that are required
for the brain to develop normally. Characterizing the inputs neces-
sary to facilitate sensory development is relatively straightforward,
but this is far more challenging in the domain of more complex
cognitive and social skills (e.g., executive functioning) and the cor-
tical regions that support these types of functions, perhaps with
the exception of language development (Kuhl, 2004). Determining
the specific environmental inputs that are necessary to scaffold the
development of these skills is critical to understand how depri-
vation in exposure to these types of experiences shapes brain
development.
Third, experimental manipulation of specific aspects of expe-
rience would allow our predictions about deprivation and neural
development to be tested in a more rigorous way. For example,
a variety of experimental improvements in environmental con-
text for children who are institutionalized would shed light on
the veracity of our model. Ideally, all children could be removed
from institutions and placed into family care; however, in societies
where that is currently impossible, providing enhanced complexity
of care could be advantageous. Potential environmental manip-
ulations include increasing enriching cognitive experiences (e.g.,
greater access to complex toys and games, greater exposure to
complex language, and more opportunities for adult instruction),
reducing caregiver-to-child ratios, and staff schedules that ensure
consistent caregiving of particular children by the same adults
over time to facilitate the formation of more selective attach-
ments as well as the provision of greater opportunities for cognitive
enrichment. Such an approach was used by the St. Petersburg-
USA Orphanage Research Team, which attempted to improve the
institutional environment by reducing caregiver-to-child ratios
and providing more consistent and responsive caregiving (The
St. Petersburg-USA Orphanage Research Team, 2008). Although this
intervention resulted in improvements in general cognitive abil-
ity, the effects on neural development are unknown. Collection of
neuropsychological and neuroimaging data following this type of
experimental design is an important next step in identifying causal
pathways through which the absence of species-typical cognitive
and social experience shapes neurodevelopment.
Fourth, despite consistencies in the neural circuitry underlying
fear learning in animals and humans, there is a surprising lack of
human research on how early threat influences fear learning across
development. As noted above, only recently have developmentally
appropriate and effective fear learning paradigms been developed
for children and adolescents (Glenn et al., 2012; Lau et al., 2011).
Examining the effects of early threat exposure on fear acquisition,
expression, extinction, and generalization as well as the underlying
neural circuitry supporting these learning processes represents a
critical area for future research.
Fifth, the issue of developmental timing of exposure and out-
come measurement is of central importance to studying the impact
of environmental experience on neural development (Hensch,
2005). Although sensitive periods in sensory and language devel-
opment have been clearly identified, progress in identifying similar
periods when the brain is particularly likely to be influenced
by more complex cognitive and social environmental inputs has
proved challenging due to measurement issues with regard to
exposure timing as well as the more complicated neural cir-
cuitry that underlies higher-order cognition. We have learned the
most about sensitive periods in social and cognitive development
from studies of institutionalization, where precise information
about the timing and duration of exposure is often available
(McLaughlin et al., 2011; Nelson et al., 2007). Consistent with the
above recommendations about the importance of experimental
manipulation, random assignment to improved environments for
children exposed to high deprivation or threat may hold the most
promise for identifying how the impact of these environments
varies according to timing and duration of exposure. An additional
possibility rarely used in the human literature involves examining
the differential impact of exposures occurring in childhood versus
 K.A. McLaughlin et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 578–591
adulthood, which has frequently been used in animal models (Chen
et al., 2006). Such an approach will determine whether early expo-
sure to deprivation and threat influences the brain in ways that are
either qualitatively or quantitatively different than adult exposure.
Sixth, longitudinal studies are needed to determine whether
disruptions in typical patterns of neural development following
deprivation and threat are, indeed, mechanisms linking these expe-
riences to the onset of psychopathology. Given evidence for greater
fear expression during conditioning paradigms, deficits in extinc-
tion learning, and disruptions in the neural circuitry underlying fear
learning and extinction among both children and adults with anx-
iety disorders (Britton et al., 2013; Craske et al., 2008; Lau et al.,
2008; Liberman et al., 2006), these pathways are likely involved
in the association between threat exposure and anxiety pathology.
The neural changes we argue to be a result of deprivation expo-
sure – including age-specific reductions in cortical thickness, poor
performance on complex cognitive tasks, and inefficient neural
recruitment during such tasks – have also been linked to exter-
nalizing disorders in numerous studies (Anderson et al., 1999;
Durston et al., 2003; Shaw et al., 2006). Moreover, age-specific
cortical thinning in association cortex has been shown to link
severe early-life deprivation to ADHD (McLaughlin et al., 2014).
However, additional studies are needed to confirm these predic-
tions.
Seventh, most adverse developmental environments are likely
to include some degree of exposure to both deprivation and threat
dimensions (Fig. 1). As such, it is important to consider how neural
consequences related to deprivation interact with those related to
threat in shaping neural development. For example, the pattern
of cortical thinning in lateral PFC and related deficits in inhibi-
tion that has been associated with exposure to deprivation (Farah
et al., 2006; McLaughlin et al., 2014; Mueller et al., 2010; Noble
et al., 2007) might interact with the heightened amygdala and
emotional reactivity to emotional stimuli associated with exposure
to threat (McCrory et al., 2013; McCrory et al., 2011) to produce
deficits not only in automatic aspects of emotion regulation, such
as fear extinction, but also in effortful emotion regulation pro-
cesses, such as cognitive reappraisal. Effortful emotion regulation
involves a more complex network including connectivity of the lat-
eral PFC and superior temporal cortex, which alters the semantic
representative of emotional stimuli and, in turn, inhibits the amyg-
dala (Buhle et al., 2014). The most pronounced deficits in these
processes would likely result from exposure to both deprivation
and threat dimensions, although this remains to be determined
empirically. Understanding how these dimensions interact to influ-
ence neural development will be necessary to understand the wide
range of negative developmental outcomes stemming from com-
plex adverse experiences.
Finally, we have focused on two dimensions of experience that
are particularly likely to impact neural development, but there
are undoubtedly others. For example, the degree of environmental
predictability has been argued to be central aspect of environ-
mental experience that shapes the development and evolution of
human life history strategies (Ellis et al., 2009), and unpredictabil-
ity or chaos in childhood predicts psychological adjustment and
early-onset sexual behavior (Belsky et al., 2012; Evans et al., 2005).
Another dimension that is like to have relevance for early neural
development is loss of an attachment figure. This is differentiated
from the frequently studied exposure of institutional rearing, which
involves complete absence of a preferential attachment figure in
early life. Loss of such a figure has been consistently linked to a
life-course persistent risk for major depression, which could be
explained by changes in development of the ventral striatum and
reward processing (Wacker et al., 2009). These highlight just two
additional dimensions of early life experience that are likely to have
meaningful effects on brain development. Future studies should
587
identify of other key dimensions of experience and characterize
their impact on the developing brain.
5. Conclusion
We propose a novel conceptual framework for understanding
the impact of childhood adversity on neural development and argue
that the field must move beyond the prevailing approach of exam-
ining the impact of complex and co-occurring exposures on brain
development to distilling those complex experiences into their core
underlying dimensions. Two important dimensions that appear to
have distinct effects on neural development are deprivation and
threat. Existing evidence from human studies provides preliminary
support for our predictions about how these types of experiences
influence neural development, although additional work is needed
to ultimately determine the utility of our conceptual framework.
We believe that such an approach will improve our understanding
of how atypical experience influences the developing brain and,
ultimately, confers risk for psychopathology.
Acknowledgements
This research was funded by the National Institutes of Men-
tal Health (K01-MH092625 to McLaughlin and K01-MH092555 to
Sheridan). The authors have no financial disclosures or conflicts of
interest to report.
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